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J. Jarczynski, T. M. Doyle, T. M. Martin, P. Latkany; Multifocal Choroiditis Pattern Prompts Identification of Familial Systemic Granulomatosis (FSG) and Three Novel Mutations in NOD2. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3892.
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To document that clinical features of multifocal choroiditis are sufficient to warrant investigation of a specific genetic etiology.
Ophthalmic examination and photography, medical history, and clinical course in 4 individuals from one family were examined in one medical clinic. Genetic analysis of NOD2 (also called CARD15 and NLRC2) was performed on genomic DNA by direct sequencing in both directions. Sample procurement and genotyping was performed under a protocol approved by the OHSU IRB.
The 14 year old female proband presented for diagnosis and management of chronic uveitis. On her first examination she was found to have a multifocal choroiditis pattern consistent with FSG. Subsequent analysis revealed that of the four family members only the proband presented with classic symptoms of FSG.Even though she denied prior familial history of FSG, the diagnosis was confirmed by genetic testing. The proband was heterozygous for three novel mutations of NOD2 encoding nonsynonymous changes at amino acid position 512 (aspartic acid to histidine), position 523 (leucine to methionine) and position 439 (arginine to histidine). One of these mutations, R439H, appeared to be inherited from the father as he was also heterozygous for this change. The other two mutations were de novo in the proband. Furthermore, none of the three mutations were found in the unaffected sibling of the proband. In addition, both the mother and sibling were heterozygous for 3 common NOD2 polymorphisms (P268S, R459R, & R587R). All three mutations are located in the NACHT domain of NOD2, where the majority of other mutations have been found. Two of them (D512H and L523M) are very near a previously reported mutation at position 513.
Multifocal choroiditis secondary to FSG by clinical appearance alone can warrant confirmation with genetic testing. Here we report a case who was found to carry three NOD2 mutations (one inherited from the father and two occurring de novo). Furthermore, we have sequenced 196 families or subjects with uveitis, related inflammatory conditions, or healthy controls and never found any of these mutations indicating that they are not common polymorphisms. Functional studies are warranted to understand further the contribution of each of these mutations to disease.
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